1. Technical Field
This invention relates to compositions and methods which are usefull for reducing hypertension in animals and humans. Specifically, it relates to antisense oligonucleotide compounds capable of binding to .beta.-1 adrenoceptor mRNA to inhibit the expression of the .beta.-1 adrenoceptor gene, and thereby decrease the total number of .beta.-adrenoceptors.
2. Background Art
.beta.-1 adrenoceptors which are distributed in the heart, kidney and blood vessels, play a role in the physiological control of blood pressure. For many years, .beta.-1 blockers, developed as drugs, have been used for the treatment of hypertension when given daily. The mechanism of control of blood pressure is not precisely known but the value of beta-blockers in hypertension control has been underscored by the reports of the Joint National Committee on High Blood Pressure recommending beta-blockers as the first line of defense in the treatment of hypertension. Current beta-blocker drugs, however, have certain disadvantages, including: (1) they have to be taken daily, or twice a day and compliance is a problem, (2) they have central effects, leading to psychological changes that contribute to the problem of patient compliance, and (3) many of the beta-blockers now available are not specific for .beta.-1 adrenoceptors and, therefore, have side effects.
Antisense oligonucleotides (AS-ONs) are single-stranded, short sequences of nucleotides which are complementary to specific messenger RNA (mRNA). AS-ONs bind to the mRNA and prevent the translation of the message into a cell product, such as protein receptor. Antisense oligonucleotides developed for the treatment of hypertension were targeted to angiotensin (AT), angiotensin receptor mRNA, angiotensinogen mRNA, and angiotensin converting enzyme mRNA. However, hypertension is a multifactorial disease; pharmacological approaches have shown that blockade of the renin-angiotensin system, or independent blockade of the .beta.-1 adrenoceptors can effectively control high blood pressure.
As can be understood from the above, there remains a need for an effective .beta.-1 adrenoreceptor blocker that is highly specific, nontoxic, produces few side effects and does not cross the blood brain barrier to produce psychological changes. Also, a beta-blocker that would last longer than a day would allow patients more flexibility in the regimen of drug dosage by taking drugs once every three to seven days.